A kind of amide derivatives and its application in treating cardiac and cerebral vascular diseases
Technical field
The present invention relates to a kind of pharmaceutical synthesis, pharmacology test and course of drug development more particularly to a kind of amides to spread out
Biology and its application in treating cardiac and cerebral vascular diseases.
Background technology
Cardiovascular and cerebrovascular disease is the general designation of angiocardiopathy and cranial vascular disease, and this kind of disease is due to hypertension, smoking
Drink, the reasons such as diabetes, dyslipidemia, metabolic syndrome cause, show as brain, heart and body tissue and ischemic occur
Or hemorrhagic lesions.As the fast development of social economy and Living consumption are constantly promoted, painstaking effort in Disease causation
The proportion that pipe disease accounts for persistently rises, increasing to Human Health Effect.
Atherosclerosis is the Etiological of cardiovascular and cerebrovascular disease, ApoE gene knockouts(ApoE-/-)It is rat aorta congee
Sample hardens(Atherosclerosis, AS)Classical model, the treatment for disease provides the platform of reliable drug screening.
Angiotensin II is combined with angiotensin receptor, shrinks whole body arteriole, vein, blood pressure raising, Hui Xin
Hypervolemia can cause human smooth muscular cells loose, and can increase the blood platelet of the rat aorta smooth muscle cell of cultured in vitro
The expression of source property growth factor so as to stimulate the hyperplasia of smooth muscle cell, and directly stimulates blood vessel hyperplasia.Therefore angiotensins
Converting enzyme inhibitor(Angiotensin converting enzyme in-hibitors, ACEI)And angiotensin receptor
Antagonist(An-giotensin receptor blockers, ARB)There is important reduce blood pressure.
Invention content
The purpose of the present invention is to provide a kind of amide derivatives, structural formula is formula(Ⅰ)
Wherein, R1Selected from H, OH or CH3, R2Selected from H, OH or CH3, R3Selected from H, OH or CH3。
Further, R1Selected from H, R2Selected from CH3, R3Selected from H;
Or R1Selected from H, R2Selected from OH, R3Selected from H;
Or R1Selected from H, R2Selected from H, R3Selected from CH3;
Or R1Selected from OH, R2Selected from H, R3Selected from H;
Or R1Selected from CH3, R2Selected from H, R3Selected from H.
Number |
Structure |
Structured data |
a |
|
LC-MS(ESI, pos, ion) m/z: 382[M+H] |
b |
|
LC-MS(ESI, pos, ion) m/z: 384 [M+H] |
c |
|
LC-MS(ESI, pos, ion) m/z: 382[M+H] |
d |
|
LC-MS(ESI, pos, ion) m/z: 384[M+H] |
e |
|
LC-MS(ESI, pos, ion) m/z: 382[M+H] |
Number is consistent with each untested compound of test example.
Further, formula(Ⅰ)The salt of the compound of expression or its solvated compounds.
Another object of the present invention is to provide a kind of amide derivatives formula(Ⅰ)Obtaining synthetic route is
Wherein, R1Selected from H, OH or CH3, R2Selected from H, OH or CH3, R3Selected from H, OH or CH3。
Further, the synthetic method of each step is as follows in said synthesis route:
(1) compound 1 being dissolved in suitable solvent, adds in DMFDMA and a small amount of triethylamine, system heating is reacted about 4 hours,
Then system is cooled to 60 DEG C, and decompression is transferred out of half solvent, and remaining system is cooled to room temperature, does not process, be directly used in down
Single step reaction.
Methanol is added in system, sodium ethoxide is added in, then adds in Pd/C catalyst, is passed through hydrogen, 30 DEG C of reactions, after
Reason obtains intermediate compound 3.
(2) compound 3 is dissolved in dichloromethane, adds in a certain amount of triethylamine, controlled low temperature, 2- is added dropwise into system
Chloracetyl chloride, is added dropwise recovery room temperature, and normal-temperature reaction 10 hours is post-treated to obtain compound 4.
(3) tertiary butyl (2- amino-2-methyls propyl) carbamate and potassium carbonate are dissolved in DMF, under nitrogen atmosphere
Compound 4 is added in, temperature reaction is for a period of time, post-treated to obtain compound 5.
(4) compound 5 is dissolved in dichloromethane, adds in trifluoroacetic acid thereto, it is post-treated after the completion of reaction to obtain
Compound 6.
(5) under room temperature, corresponding carboxylic acid derivates and pyridine are dissolved in dichloromethane, after adding in DCC stirring a period of times,
Compound 6 is added thereto, system is stirred overnight, post-treated to obtain corresponding carboxylic acid derivates.
Further, the reaction dissolvent in the step (1) is one kind in DMF, DMAC, THF, preferably DMF.
Further, the heating reaction temperature of the step (1) is 70 DEG C~120 DEG C, preferably 95 DEG C~100 DEG C.
Further, the low temperature dropping temperature of the step (2) is 5 DEG C~15 DEG C, preferably 10 DEG C.
Further, the reaction temperature in the step (3) is 60 DEG C~90 DEG C, preferably 70 DEG C~80 DEG C.
The ApoE that amide derivatives of the present invention mediate Angiotensin II-/-It is shown in mouse model
Good bioactivity illustrates that amide derivatives of the present invention have in preventing and/or treating cardiovascular and cerebrovascular disease
Positive effect can carry out more in-depth study in terms of hypertension, hyperlipidemia and/or atherosclerosis.
Another object of the present invention is to provide a kind of amide derivatives formula(Ⅰ)Preparing prevention and/or treatment
Application in cardiovascular and cerebrovascular diseases medicament.
Further, the cardiovascular and cerebrovascular disease refers to hypertension, hyperlipidemia and/or atherosclerosis.
Another object of the present invention is to provide a kind of amide derivatives formula(Ⅰ)Preparing prevention and/or treatment
Application in abdominal aorta tumor medicine.
Further, the amide derivatives formula(Ⅰ)In treatment hypertension, hyperlipidemia and/or atherosclerosis
Meanwhile have both the purposes that prevention abdominal aneurvsm occurs.
Obviously, the above according to the present invention according to the ordinary technical knowledge and means of this field, is not departing from this hair
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Specific embodiment
Embodiment 1:N- (2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- first
Base propyl)-(5- picolines) -2- formamides synthesis
(1)5- hydroxyl -1H- pyrroles [3,2] and the synthesis of pyridine
6- methyl-5-nitros -2 hydroxy pyrimidine (10 mmol) is added in 50 ml DMF, the complete molten rear addition N of stirring, N- diformazans
Amide formal (12 mmol) then adds in 0.7 ml triethylamines thereto again, and system is heated to 95-100 DEG C, keeps temperature
Reaction 4 hours.Reaction system is cooled to 60 DEG C or so, and decompression is transferred out of half solvent, and remaining system is cooled to 25 DEG C or so.Institute
The solution for obtaining intermediate 2 is not further processed, and is directly entered and is reacted in next step.
50 ml methanol are added in the system of previous step, 0.82 g sodium acetates are added thereto, then add in 0.8 g
Pd/C is passed through hydrogen, replaces three times, and making system, 30 DEG C are reacted 4 hours full of hydrogen.Catalyst, filtrate are removed by membrane filtration
Solvent is removed under reduced pressure at 45 DEG C, is dissolved with a small amount of dichloromethane, and flash column chromatography separation obtains 1.15 g white crystalline 5- hydroxyls
Base -1H- pyrroles [3,2] and pyridine, yield 86%.Need to highlight is:5- hydroxyl -1H- pyrroles [3,2] and the hydroxyl of pyridine
Base remains into final product always in subsequent reactions, and the present invention has equally synthesized a series of without this hydroxyl in the course of the research
Compound, but pharmacological activity it was found that without this hydroxyl compound activity be far below with this hydroxyl chemical combination
Object.1H-NMR (400 MHz, CDCl3) δ:4.53(s, 1H), 6.54(d, 1H), 7.01(d, 1H), 7.41(d,
1H), 7.78(s, 1H), 8.03(d, 1H). 13C-NMR(75 MHz, CDCl3) δ: 107.65, 109.06,
119.77, 126.27, 128.68, 142.13, 151.75. LC-MS(ESI, pos, ion) m/z: 135 [M+H]。
(2)The synthesis of the chloro- 1- of 2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases)-ethyl ketone
5- hydroxyl -1H- pyrroles [3,2] and pyridine (10 mmol) are dissolved in 40 ml dichloromethane solutions, add in 10 ml thereto
Triethylamine, control temperature are added dropwise to the dichloromethane solution of 2- chloracetyl chlorides (12 mmol) into system less than 10 DEG C, are added dropwise
After restore room temperature, stirring at normal temperature 10 hours, then with the aqueous sodium carbonate washing reaction system of 50 ml 5%, organic phase
Use anhydrous Na2SO4Dry, after solvent evaporated, obtained solid flash column chromatography detaches, and obtains the chloro- 1- of the light yellow 2- of 1.9 g
(5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases)-ethyl ketone solid, yield 90%.1H-NMR (400 MHz, CDCl3) δ:
4.71(s, 2H), 6.45(d, 1H), 6.54(d, 1H), 8.09(d, 1H), 8.76(d, 1H). 13C-NMR(75
MHz, CDCl3) δ: 42.91, 110.55, 115.56, 122.25, 127.21, 130.14, 137.60, 154.06,
163.78. LC-MS(ESI, pos, ion) m/z: 211[M+H]。
(3)Tertiary butyl-(2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- first
Base propyl) amino methyl synthesis
In the glass flask of the 200ml capacity equipped with agitating device, thermometer, reflux condenser and dropping funel, by tertiary fourth
The N of base (2- amino-2-methyls propyl) carbamate (10mmol), potassium carbonate (11mmol) and 12 ml, N- dimethyl methyls
Amide adds in a nitrogen atmosphere.While being stirred at room temperature, 2- chloro- 1- (5- hydroxyl -1H- pyrroles [3,2] and pyrrole are added in
Pyridine -1- bases)-ethyl ketone (11mmol), mixture is made to react 3 ~ 4 hours at 70 80 DEG C.It is after the completion of reaction, mixture is cold
But to room temperature, 40 ml toluene are then added in.After being washed twice with water (50ml), dried with magnesium sulfate.After filtering, it is concentrated under reduced pressure.
Then silica gel column chromatography (packing material is used:Wakogel C-200, eluent:Hexane/ethyl acetate=1/2 (volume
Than)) obtained yellow oil is refined.3.4 g off-white colors tertiary butyls-(2- ((2- (5- hydroxyl -1H- pyrroles [3,
2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-propyls) amino methyl solid (yield 94%), purity 99% (passes through
The area percentage of high performance liquid chromatography).1H-NMR (400 MHz, CDCl3) δ: 1.27(s, 6H), 1.41(s,
9H), 1.82(s, 1H), 3.12(s, 1H), 3.50(s, 1H), 3.78(d, 2H), 4.14(s, 1H), 6.43(d,
1H), 6.52(d, 1H), 8.00(d, 1H), 8.67(d, 1H). 13C-NMR(75 MHz, CDCl3) δ: 25.66,
28.33, 47.13, 47.35, 51.12, 80.89, 110.55, 115.56, 122.25, 127.21, 130.14,
137.60, 154.06, 157.93, 168.18. LC-MS(ESI, pos, ion) m/z: 363[M+H]。
(4)2- ((1- amino-2-methyl propyl -2- bases) amino) -1- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1-
Base) ethyl ketone synthesis
By tertiary butyl-(2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-props
Base) amino methyl (10 mmol) is dissolved in 30 ml dichloromethane, trifluoroacetic acid (15 mmol) is added in thereto.System is 30
It stirs 4 hours under the conditions of DEG C, is completed until TLC detects reaction, with 10% aqueous sodium carbonate 20ml × twice of 2 washing, organic phase
It is dried with anhydrous sodium sulfate, after filtering, solvent evaporated under the conditions of filter vacuum obtains 2.4 g off-white colors 2- ((1- amino-2-methyls
Propyl -2- bases) amino) -1- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) ethyl ketone crystal, yield 92%.1H-NMR
(400 MHz, CDCl3) δ: 1.26(s, 6H), 1.85(s, 2H), 2.64(s, 2H), 2.84(s, 1H), 3.73
(s, 1H), 3.85(s, 1H), 6.42(d, 1H), 6.51(d, 1H), 7.98(t, 2H). 13C-NMR(75 MHz,
CDCl3) δ: 24.37, 47.35, 48.29, 50.15, 110.55, 115.56, 122.25, 127.21, 130.14,
137.6, 154.06, 168.18. LC-MS(ESI, pos, ion) m/z: 263[M+H]。
(5)N- (2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-props
Base)-(5- picolines) -2- formamides synthesis
In 25 DEG C and N2Under atmosphere, to 5- picoline -2- formic acid(12 mmol)And pyridine(20 mmol)20 mL anhydrous two
1,3- dicyclohexylcarbodiimides DCC is added in chloromethanes solution(15 mmol).After five minutes, 2- ((1- amino -2- first is added in
Base propyl -2- bases) amino) -1- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) ethyl ketone(10 mmol), and will mixing
Object is stirred overnight.TLC(95:5 dichloromethane:Methanol containing 2% ammonia)Show that all raw materials are all consumed.Reaction is used
Sodium bicarbonate is quenched and is filtered by plug of celite.Plug is rinsed with dichloromethane, and water layer is extracted with dichloromethane.By merging
Organic layer Na2SO4It after drying, filters and concentrates in vacuo, obtains 3.4 g light tan solids.Crude product is pure by flash chromatography
Change, use 2% ~ 8% MeOH:The gradually gradient of dichloromethane and 2% ammonia is purified, and obtains 3.2 g white powders N-
(2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-propyls)-(5- methyl pyrroles
Pyridine) -2- formamides, yield 89%.1H-NMR (400 MHz, CDCl3) δ: 1.27(s, 6H), 1.66(s, 1H),
2.32(s, 3H), 3.14(d, 2H), 3.77(d, 2H), 4.55(s, 1H), 6.44(m, 3H), 8.03(m, 3H),
8.21(d, 1H), 8.61(m, 1H). 13C-NMR(75 MHz, CDCl3) δ: 18.43, 25.66, 47.35,
48.08, 51.12, 110.55, 115.56, 122.25, 124.95, 127.21, 130.14, 136.91, 137.33,
137.6, 148.21, 148.7, 154.06, 168.18, 168.27. LC-MS(ESI, pos, ion) m/z: 382[M
+H]。
Embodiment 2:N- (2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- first
Base propyl)-(5- pyridones) -2- formamides synthesis
In 25 DEG C and N2Under atmosphere, to 5- pyridone -2- formic acid(12 mmol)And pyridine(20 mmol)20 mL anhydrous two
1,3- dicyclohexylcarbodiimides DCC is added in chloromethanes solution(15 mmol).After five minutes, 2- ((1- amino -2- first is added in
Base propyl -2- bases) amino) -1- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) ethyl ketone(10 mmol), and will mixing
Object is stirred overnight.TLC(95:5 dichloromethane:Methanol containing 2% ammonia)Show that all raw materials are all consumed.Reaction is used
Sodium bicarbonate is quenched and is filtered by plug of celite.Plug is rinsed with dichloromethane, and water layer is extracted with dichloromethane.By merging
Organic layer Na2SO4It after drying, filters and concentrates in vacuo, obtains 3.4 g light tan solids.Crude product is pure by flash chromatography
Change, use 2% ~ 8% MeOH:The gradually gradient of dichloromethane and 2% ammonia is purified, and obtains 3.3 g white powders N-
(2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-propyls)-(5- hydroxyl pyrroles
Pyridine) -2- formamides, yield 89%.LC-MS(ESI, pos, ion) m/z: 384[M+H].
Embodiment 3:N- (2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- first
Base propyl)-(4- picoline -2- bases)-formamide synthesis
In 25 DEG C and N2Under atmosphere, to 4- picoline -2- formic acid(12 mmol)And pyridine(20 mmol)20 mL anhydrous two
1,3- dicyclohexylcarbodiimides DCC is added in chloromethanes solution(15 mmol).After five minutes, 2- ((1- amino -2- first is added in
Base propyl -2- bases) amino) -1- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) ethyl ketone(10 mmol), and will mixing
Object is stirred overnight.TLC(95:5 dichloromethane:Methanol containing 2% ammonia)Show that all raw materials are all consumed.Reaction is used
Sodium bicarbonate is quenched and is filtered by plug of celite.Plug is rinsed with dichloromethane, and water layer is extracted with dichloromethane.By merging
Organic layer Na2SO4It after drying, filters and concentrates in vacuo, obtains 3.3 g light tan solids.Crude product is pure by flash chromatography
Change, use 2% ~ 8% MeOH:The gradually gradient of dichloromethane and 2% ammonia is purified, and obtains 3.1 g white powders N-
(2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-propyls)-(4- methyl pyrroles
Pyridine -2- bases)-formamide, yield 89%.LC-MS(ESI, pos, ion) m/z: 382 [M+H].
Embodiment 4:N- (2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- first
Base propyl)-(6- pyridone -2- bases)-formamide synthesis
In 25 DEG C and N2Under atmosphere, to 6- pyridone -2- formic acid(12 mmol)And pyridine(20 mmol)20 mL anhydrous two
1,3- dicyclohexylcarbodiimides DCC is added in chloromethanes solution(15 mmol).After five minutes, 2- ((1- amino -2- first is added in
Base propyl -2- bases) amino) -1- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) ethyl ketone(10 mmol), and will mixing
Object is stirred overnight.TLC(95:5 dichloromethane:Methanol containing 2% ammonia)Show that all raw materials are all consumed.Reaction is used
Sodium bicarbonate is quenched and is filtered by plug of celite.Plug is rinsed with dichloromethane, and water layer is extracted with dichloromethane.By merging
Organic layer Na2SO4It after drying, filters and concentrates in vacuo, obtains 3.5 g light tan solids.Crude product is pure by flash chromatography
Change, use 2% ~ 8% MeOH:The gradually gradient of dichloromethane and 2% ammonia is purified, and obtains 3.2 g white powders N-
(2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-propyls)-(6- hydroxyl pyrroles
Pyridine -2- bases)-formamide, yield 94%. LC-MS(ESI, pos, ion) m/z: 384[M+H].
Embodiment 5:N- (2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- first
Base propyl)-(6- picoline -2- bases)-formamide synthesis
In 25 DEG C and N2Under atmosphere, to 6- picoline -2- formic acid(12 mmol)And pyridine(20 mmol)20 mL anhydrous two
1,3- dicyclohexylcarbodiimides DCC is added in chloromethanes solution(15 mmol).After five minutes, 2- ((1- amino -2- first is added in
Base propyl -2- bases) amino) -1- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) ethyl ketone(10 mmol), and will mixing
Object is stirred overnight.TLC(95:5 dichloromethane:Methanol containing 2% ammonia)Show that all raw materials are all consumed.Reaction is used
Sodium bicarbonate is quenched and is filtered by plug of celite.Plug is rinsed with dichloromethane, and water layer is extracted with dichloromethane.By merging
Organic layer Na2SO4It after drying, filters and concentrates in vacuo, obtains 3.4 g light tan solids.Crude product is pure by flash chromatography
Change, use 2% ~ 8% MeOH:The gradually gradient of dichloromethane and 2% ammonia is purified, and obtains 3.3 g white powders N-
(2- ((2- (5- hydroxyl -1H- pyrroles [3,2] and pyridine -1- bases) -2- ethyoxyls) amino) -2- methyl-propyls)-(6- methyl pyrroles
Pyridine -2- bases)-formamide, yield 89%. LC-MS(ESI, pos, ion) m/z: 382[M+H].
Test example:
By the ApoE of 16 weeks males-/-Mouse be randomly divided into control group and several experimental groups to be measured, then with penta bar of 0.1% ratio
Appropriate sodium anesthesia, is subcutaneously embedded to mini-pump(Model2004, Alzet, Cupertino, CA), addition physiological saline solution in pump
Angiotensin II(Sigma), can be with the dosage continued administration surrounding of 1000ng/kg/min.From first post-operative day
It rises, pinpoints gavage to mouse daily, experimental group to be measured is untested compound(10mg/kg), control group is the water of equivalent.Gavage 28
It draws materials after it.Mouse is taken blood pressure and is weighed using BP-89A blood pressure measurings with tail sleeve method.Mouse takes eye socket blood, and 6000 turns of blood plasma/
Point, supernatant is taken after centrifugation in 10 minutes, measures the blood lipid level of mouse.It is shown in Table 1.
The ApoE that table 1 mediates Angiotensin II-/-The influence of mouse
It can be obtained by upper table, the ApoE of the compound on vascular Angiotensin Converting Enzyme II mediations prepared by the present invention-/-The blood pressure of mouse is equal
There is different degrees of reduction, illustrate that the compound prepared by the present invention can reduce the blood pressure raising of Angiotensin II mediation.
In addition, the compound prepared by the present invention can be different degrees of reduction mice plasma in cholesterol, triglycerides and low-density
The level of lipoprotein illustrates that the compound prepared by the present invention has the function of regulating plasma lipid, can be used as reducing blood lipid and/or artery
The drug candidate of atherosis carries out more deep pharmaceutical research.
Mouse is put to death, fixed and separating mouse abdominal aorta.Counting abdominal aneurvsm, a situation arises, the results are shown in Table
2:
The ApoE that table 2 mediates Angiotensin II-/-The influence that a situation arises of mouse abdominal aneurvsm
A situation arises that statistics is found for mouse abdominal aneurvsm, in 15 mouse have one during the experiment in control group because
The rupture of abdominal aneurvsm and it is dead, in remaining 14 mouse, bury pump the 28th day after have 6 generation abdominal aneurvsms, by because
The rupture of abdominal aneurvsm and it is dead and generate abdominal aneurvsm joint account, obtain the incidence of abdominal aneurvsm.
The incidence of different trial drug group mouse abdominal aneurvsms has different degrees of drop as can be seen from the above table
It is low, and number the incidence 10% of compound abdominal aneurvsm for being d, illustrate compound prepared by the present invention prevention and/
Or have positive effect in treatment abdominal aneurvsm, it can effectively prevent abdomen especially in the treatment of hypertension or hyperlipidemia actively
The generation of arteries and veins knurl provides a new Research Thinking for hypertension, high blood cholesterol drug research and development.